Amyloidosis

May 4, 2015

Alnylam Pharmaceuticals reported
results of a phase II, open-label extension
(OLE) study of patisiran for the treatment
of transthyretin (TTR)-mediated amyloidosis
(ATTR amyloidosis) in patients with familial
amyloidotic polyneuropathy (FAP). The ongoing
OLE study is an open-label, multicenter
trial evaluating patisiran administration in
FAP patients who previously were enrolled in
a phase II study. Patisiran is being administered
once every three weeks at a dose of
0.3mg/kg by intravenous infusion. Study
results showed a mean 2.5 point decrease
in modified Neuropathy Impairment Score
(mNIS+7) at 12 months in patients who had
reached the 12-month endpoint (N=20) at
the time of data cutoff. This decrease in neuropathy
progression compares favorably to
the 13-to-18-point increase in mNIS+7 at 12
months that can be estimated from the literature
in untreated FAP patients with similar
baseline characteristics. In addition, patisiran
treatment achieved a sustained mean serum
TTR knockdown at the 80% target level for
approximately 16 months, with an up to 88%
mean knockdown achieved between doses.
Patisiran also was found to be generally well-tolerated
out to 17 months of drug administration,
with no drug-related serious adverse
events to date; all 27 patients enrolled in the
study continue to receive patisiran.

November 25, 2013

Alnylam Pharmaceuticals issued results
of its phase II trial of patisiran (ALNTTR02),
an RNAi therapeutic targeting the
transthyretin (TTR) gene for the treatment
of TTR-mediated amyloidosis (ATTR). The
international study in 29 patients was
an open-label, multi-center, multi-dose,
dose-escalation trial. Patients received two
doses of patisiran in five cohorts with doses
ranging from 0.01mg/kg to 0.30mg/kg,
using either a once-every-four-week or
once-every-three-week dosing regimen.
As compared with the lowest dose group
of 0.01mg/kg, there was a statistically
significant knockdown of serum TTR at
doses of 0.15mg/kg (p<0.05) and
0.30mg/kg (p<0.001). The study results
support further evaluation of patisiran at
the 0.30mg/kg dose administered once
every three weeks. With this dose and
regimen, mean TTR knockdown at nadir of
83.8% and 86.7% was observed following
the first and second doses, respectively,
with maximum TTR knockdown of up to
96.0%. Results showed 1:1 correspondence
in knockdown of mutant and wild-type
TTR (r2=0.95, p<0.001), with essentially
superimposable pharmacodynamic effects
toward both protein species. Serum TTR
knockdown was highly correlated with a
reduction in circulating levels of retinol
binding protein (RBP) (r2=0.89, p<0.001)
and vitamin A (r2=0.90, p<0.001). Alnylam
plans to develop and commercialize the
ALN-TTR program globally.

September 16, 2013

Alnylam Pharmaceuticals reported results of phase I trials of ALN-TTR01 and ALNTTR02 for the treatment of TTR-mediated amyloidosis (ATTR). Both trials were designed as multi-center, randomized, single-blind, placebo-controlled, dose-ranging studies in patients with ATTR (n=32) for ALN-TTR01, or in healthy adult volunteers (n=17) for ALN-TTR02. Results of the ALN-TTR01 study demonstrated a dose-dependent reduction in serum TTR levels with a statistically significant mean reduction of 38% at approximately day 7 to 10 in the 1.0mg/kg group (p<0.05). Analysis revealed both mutant and wild-type TTR were similarly affected. Mild-to-moderate acute infusion reactions were observed in 20.8% of patients receiving ALN-TTR01 as a 15-minute infusion. There were no significant increases in liver function test parameters. Results of the ALN-TTR02 study demonstrated substantial knockdown of serum TTR in all participants receiving doses of 0.15mg/kg to 0.50mg/kg. Knockdown was rapid, potent and durable, with highly significant changes, as compared to placebo (p<0.001), and minimal variability among participants in both the kinetics of the response and maximal levels of TTR suppression. At doses as low as 0.15mg/kg, substantial serum TTR suppression was achieved, with a mean 81.9% knockdown at nadir. At a dose of 0.30mg/kg, an 86.8% mean knockdown was achieved at nadir, with a mean 66.7% reduction still observed 28 days post-dose. Serum TTR reductions were highly correlated with parallel changes in retinol binding protein (RBP) (r2=0.83) and vitamin A levels (r2=0.86). ALNTTR02 administered as a 60-minute infusion produced no serious adverse events associated with the drug up through 0.30mg/kg.

July 22, 2013

Alnylam Pharmaceuticals issued results from a phase I trial of ALN-TTRsc for the treatment of TTR-mediated amyloidosis (ATTR). The randomized, double-blind, placebo-controlled, single- and multidose, dose-escalation study enrolled 40 healthy subjects in the U.K. Subjects received single or multiple-ascending subcutaneous doses of ALN-TTRsc ranging from 1.25mg/kg to 10mg/kg. The primary objective of the study is to evaluate the safety and tolerability of single and multiple doses of subcutaneously administered ALN-TTRsc. Secondary objectives include assessment of clinical activity of the drug as measured by serum TTR levels. Upon completion, the company plans to start a phase II clinical study of ALN-TTRsc in familial amyloidotic cardiomyopathy (FAC) patients in late 2013 and, assuming positive results, expects to start a phase III trial for ALN-TTRsc in FAC patients in 2014.

July 15, 2013

Alnylam Pharmaceuticals released results from a phase II trial of ALN-TTR02 for the treatment of TTR-mediated amyloidosis (ATTR). The open-label, multi-center, multidose, dose-escalation trial to evaluate the safety and tolerability of two doses of ALNTTR02 and to demonstrate clinical activity based on serial measurement of circulating serum levels of wild-type and mutant TTR was designed to treat up to 30 ATTR polyneuropathy patients with ALN-TTR02 administered at doses of 0.01mg/kg to 0.30mg/kg, using either a once-every-four-week or once-every-three-week dosing regimen. As compared with the lowest dose group of 0.01mg/kg, there was a statistically significant knockdown of serum TTR at doses of 0.15mg/kg (p<0.01) and 0.30mg/kg (p<0.001). At 0.30mg/kg administered once every four weeks, mean TTR knockdown at nadir of 82.6% and 84.8% was observed following the first and second doses, respectively, and maximum TTR knockdown was up to 90.8%. At 0.30mg/kg administered once every three weeks, mean TTR knockdown at nadir of 83.1% and 87.4% was observed following the first and second doses, respectively, and maximum TTR knockdown was up to 92.8%. The company remains on track to initiate in mid-2013 an open-label extension study of ALN-TTR02 for patients treated in the phase II study.

July 23, 2012

Alnylam Pharmaceuticals announced positive topline results from a phase I trial of ALN-TTR02 for the treatment of transthyretin (TTR)-mediated amyloidosis (ATTR). This randomized, single-blind, placebo-controlled, single-ascending dose study completed treatment in 17 healthy patients enrolled into five sequential cohorts of increasing doses ranging from 0.01 to 0.50mg/kg. Preliminary data showed a single dose of ALN-TTR02 resulted in rapid, dose-dependent, durable and specific knockdown of serum TTR levels. The drug achieved up to 94% reduction of serum TTR and a nearly 80% level of TTR suppression that was sustained at one month. This suppression was observed at doses as low as 0.15mg/kg, with a mean 81.9% knockdown at nadir. In subjects treated with 0.30mg/kg, an 86.8% mean knockdown was achieved at nadir, and a mean 66.7% reduction was observed 28 days post-dose. In the one patient treated with the 0.50mg/kg dose, knockdown of 93.8% was demonstrated at nadir, with 76.8% reduction maintained at day 28. ALN-TTR02 was generally safe and well tolerated, with no significant treatment-emergent adverse events. Based on the positive results, Alnylam is advancing ALN-TTR02 into a phase II dose-escalation trial.

May 21, 2012

Alnylam Pharmaceuticals reported results from a phase I trial of ALN-TTR01 for the treatment of transthyretin-mediated amyloidosis (ATTR). This randomized, placebo-controlled, single-dose escalation study enrolled 32 patients. Subjects were enrolled in seven sequential cohorts of increasing doses ranging from 0.01 to 1.0mg/kg or placebo. ALN-TTR01 demonstrated a dose-dependent reduction in serum TTR levels with a statistically significant mean reduction of 38% at approximately day seven to 10 in the 1.0mg/kg group (geometric mean relative to placebo, p&equiz;0.01). One patient exemplified the rapid onset of ALN-TTR01, who after one dose showed 63% TTR lowering at 48 hours, peak TTR knockdown of 81% at day 10, approximately 50% lowering at 30 days post-dose and full recovery at 60 days. ALN-TTR01 was found to be generally safe and well tolerated. Mild-to-moderate acute infusion reactions were observed in five of 24 (20.8%) patients receiving ALN-TTR01 and were readily managed by slowing of the infusion rate where necessary. Alnylam will use the data to advance ALN-TTR02 to phase II in the second half of 2012.

November 28, 2011

Alnylam Pharmaceuticals issued preliminary results from a phase I trial of ALN-TTR01 for the treatment of TTR-mediated amyloidosis (ATTR). Data are from 31 subjects enrolled in this randomized, placebo-controlled, single-dose escalation study. The subjects were placed in seven sequential cohorts of increasing doses ranging from 0.01 to 1.0 mg/kg. ALN-TTR01 demonstrated a dose-dependent reduction in serum TTR levels with a statistically significant mean 41% reduction at the 1.0 mg/kg dose level relative to placebo (p≡0.02). All subjects in the 1.0 mg/kg group (n≡5) showed lowering of serum TTR protein which ranged from 25 to 81%. Nadir levels were achieved approximately seven days after dosing and serum TTR levels remained decreased through at least 24 days. One subject in the 1.0 mg/kg dose group showed 63% lowering at 48 hours, peak suppression of 81% at 7 days, and approximately 50% lowering of serum TTR protein at 28 days post dose. ALN-TTR01 was well tolerated and there were no serious adverse events.

April 18, 2011

Pfizer issued results from a phase II/III trial of tafamidis for the treatment of Transthyretin Familial Amyloid Polyneuropathy. This open-label, 12-month extension study (Fx-006) was conducted to evaluate long-term safety and efficacy in 86 subjects who completed an 18-month pivotal study. All subjects received tafamidis 20 mg orally once-daily for 12 months; the subjects randomized to placebo in the previous study crossed over to active drug. Data showed that earlier treatment with tafamidis resulted in better outcomes. Subjects treated with tafamidis for 30 months had less neurologic deterioration than those who began tafamidis 18 months later, showing a 55.9% preservation of function as measured by the Neuropathy Impairment Score-Lower Limb (NIS-LL), or a mean change from baseline of 3.0 for those treated for 30 months versus 6.8 for those initiating treatment 18 months later (p≡0.04). In addition, subjects treated with tafamidis over 30 months showed preservation in large nerve fiber function (66% preservation or 1.6 versus 4.7 for those treated 18 months later, p≡0.007) and small nerve fiber function (45.5% or 1.2 versus 2.2 for those treated 18 months later.

April 25, 2005

Neurochem issued negative results of a phase II/III trial of Fibrillex, for the treatment of Amyloid A (AA) amyloidosis. Study data did show a trend towards statistical improvement in the number of patients achieving stable or improved disease states vs. placebo (13.4% more subjects; p=0.06), but failed to meet the primary p-value endpoint of p<0.01. Secondary endpoints, including progression to end-stage renal failure/dialysis and slope of decline of creatinine clearance, suggested that the drug was active in the disease. This double-blind, placebo-controlled study enrolled 183 subjects with AA amyloidosis, who received Fibrillex (n= 89) or placebo (n=94) for 24 months. The company announced that they do plan to continue the development of Fibrillex, and that they would meet with the FDA in the near future to discuss the next steps in development.

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